Recurrent or Progressive Glioblastoma following Initial Therapy

Primary objective: The primary objective is to compare the overall survival (OS) between treatment with DSP-7888 Dosing Emulsion plus bevacizumab (Bev) versus Bev alone in patients with recurrent or progressive glioblastoma multiforme (GBM) following initial therapy. Secondary objectives: • To compare the 12-month survival of DSP-7888 Dosing Emulsion plus Bev to Bev alone • To compare the progression-free survival (PFS) of DSP-7888 Dosing Emulsion plus Bev to Bev alone • To compare the 6-month PFS of DSP-7888 Dosing Emulsion plus Bev to Bev alone • To compare the response rate of DSP-7888 Dosing Emulsion plus Bev to Bev alone • To compare the duration of response of DSP-7888 Dosing Emulsion plus Bev to Bev alone • To describe the adverse event (AE) profile of DSP-7888 Dosing Emulsion plus Bev Exploratory objectives: • To describe the relationship between pharmacodynamic parameters such as Wilms’ Tumor 1 (WT1) peptide-specific cytotoxic T lymphocyte (CTL) activity and certain clinical findings (eg, OS, response) in patients receiving DSP-7888 Dosing Emulsion plus Bev • To describe the relationship between expression of WT1 and programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) in tumor tissue and certain clinical findings (eg, OS, response) in patients receiving DSP-7888 Dosing Emulsion plus Bev • To collect diffusion-weighted imaging for future analysis of imaging findings and correlation with disease progression

DSP-7888

DSP-7888 is a cocktail peptide vaccine consisting of two
synthetic peptide

Injection

10.5, 3.5, 1.75

Primary Endpoint
The primary endpoint will be OS and is defined as the interval between randomization and
death from any cause. Patients who are lost to follow-up will be censored on the last day
they were known to be alive.

Secondary Endpoints
The secondary endpoints will be:
• The 12-month survival is defined as the proportion of patients alive 12 months after
randomization.
• Progression-free survival is defined as the interval between randomization and
progression or death from any cause.
• 6-month PFS is defined as the proportion of patients alive at 6 months after
randomization and without progressive neoplastic disease.
• The response rate is defined as the proportion of patients exhibiting a response
(complete response [CR] plus partial response [PR]) based on the RANO criteria as
determined by the central radiology body.
• The duration of response is defined as the interval between first documented
oncological response and progression of disease or death from any cause, with
response based on the RANO criteria as determined by the central radiology body

Inclusion Criteria
The study will enroll patients with GBM whose tumors have recurred or progressed
following initial treatment with surgery, radiation, and chemotherapy. To be eligible for
study entry, patients must satisfy all of the following criteria:
1. Patients or their legal representatives must be able to provide written informed
consent.
2. Histologically confirmed diagnosis of supratentorial GBM (Grade 4
astrocytoma).
3. Radiographic evidence of first recurrence or progression of GBM following
primary therapy consisting of surgery (biopsy or resection) and chemoradiation;
patients may have undergone a second debulking surgery following initial
recurrence or progression. Patients whose tumors are O6
-methyl-guanyl-methyltransferase (MGMT) methylated-promoter negative need not have received
chemotherapy in the past to be eligible.
4. Human leukocyte antigen (HLA) type HLA-A*02:01, HLA-A*02:06, or
HLA-A*24:02.
5. Age ≥18.
6. Karnofsky Performance Status (KPS) score of ≥60.
7. Serum creatinine value <2X the upper limit of normal (ULN) for the reference
laboratory.
8. Alanine aminotransferase (AST)/aspartate aminotransferase (ALT) <3X the
ULN and total bilirubin <2X the ULN for the reference laboratory.
9. Men and women of childbearing potential must agree to use a reliable method of
contraception (oral contraceptives, implantable hormonal contraceptives, or
double barrier method) or agree to completely refrain from heterosexual
intercourse for the duration of the study and for 180 days following the last dose
of DSP-7888 Dosing Emulsion.
10. Patients must have recovered from the effect of all prior therapy to Grade 2 or
less.
11. Patients must be at least 28 days from any major surgery, and any surgery
incisions or wounds must be completely healed.
12. Patients must be at least 12 weeks from the completion of prior RT in order to
discriminate pseudo-progression of disease from progression.
13. Patients must be at least 4 weeks from the completion of prior systemic or
intracranial chemotherapy.
14. For patients who are not receiving therapeutic anticoagulation treatment, an
international normalized ratio (INR) and a PTT ≤ 1.5 × the ULN; patients who
are receiving anticoagulation treatment should be on a stable dose.

Exclusion Criteria
Patients will be excluded from the study if one or more of the following criteria are
applicable:
1. Prior therapy with Bev.
2. Any anti-neoplastic therapy, including RT, for first relapse or recurrence.
3. Evidence of leptomeningeal spread of tumor or any history, presence, or
suspicion of metastatic disease extracranially.
4. Evidence of impending herniation on imaging.
5. Patients with infections that have required treatment with systemic antibiotics
within 7 days of first dose of protocol therapy.
6. The need for systemic glucocorticoids in doses in excess of 4 mg/day of
dexamethasone or in comparable doses with other glucocorticoids.
7. Treatment with any investigational agents within 5 half-lives of the agent in
question or, if the half-life is unknown, within 28 days of enrollment.
8. Pregnant or lactating females.
9. Prior history of malignancy within 3 years of enrollment other than basal or
squamous cell carcinoma of the skin, cervical intra-epithelial neoplasia, in situ
carcinoma of the breast, or prostate cancer treated with surgery or RT with a
prostate specific antigen of <0.01 ng/mL.
10. Patients with active autoimmune diseases within 2 years of enrolment into the
study including, but not limited to, rheumatoid arthritis, systemic lupus
erythematosus, systemic sclerosis, Sjogren’s syndrome, Wegener’s
granulomatosis, ulcerative colitis, Crohn’s disease, myasthenia gravis, Graves’
disease, or uveitis except for psoriasis not requiring systemic therapy, vitiligo or
alopecia areata, or hypothyroidism; if an autoimmune condition has been
clinically silent for 12 months or greater, the patient may be eligible for
enrolment.
11. Patients on immunosuppressive therapies; the use of topical, inhalational,
ophthalmologic or intra articular glucocorticoids, or the use of physiologic
replacement doses of glucocorticoids are permitted.
12. Patients with primary immunodeficiency diseases.
13. Patients with significant bleeding in the preceding 6 months or with known
coagulopathies.
14. History of abdominal fistula, intestinal perforation, or intra-abdominal abscess in
the preceding 12 months.
15. Positive serology for human immunodeficiency virus (HIV) infection, active
hepatitis B, or untreated hepatitis C; patients who have completed a course of
anti-viral treatment for hepatitis C are eligible.
16. Significant cardiovascular disease, including New York Hospital Association
Class III or IV congestive heart failure, myocardial infarction within 6 months of
enrollment, unstable angina, poorly controlled cardiac arrhythmias, or stroke
within the preceding 6 months.
17. Any other uncontrolled inter current medical condition, including systemic
fungal, bacterial, or viral infection; uncontrolled hypertension; diabetes mellitus;
or chronic obstructive pulmonary disease requiring 2 or more hospitalizations in
the preceding 12 months.
18. Any psychiatric condition, substance abuse disorder, or social situation that
would interfere with a patient’s cooperation with the requirements of the study.
19. Known sensitivity to Bev or any of the components of DSP-7888 Dosing
Emulsion.